Herpes zoster virus is one of herpes virus group. Herpes viruses are DNA viruses with double-stranded DNA genomes, a regular icosahedron capsid, and an envelope derived from the nuclear membrane of the host cell. There are eight types of human herpes viruses including 1) herpes simplex virus type 1 (HSV-1), 2) herpes simplex virus type 2 (HSV-2), 3) varicella zoster virus (VZV), 4) Epstein-Barr virus (EBV), 5) cytomegalovirus (CMV), 6) human herpes virus type 6, 7) human herpes virus type 7 and 8) human herpes virus type 8. Herpesviridae viruses establish latent infections after initially infecting the human body. They are re-activated when the human host becomes immunocompromised to cause a diseased condition (recurrence). In other words, the primary infection is an exogenous infection from hosts or environments having viruses (horizontal infection or vertical infection). Recurrence is an intrinsic infection from within. The VZV lies in particular hidden in the ganglions. It is re-activated when the host becomes immunocompromised and produces rashes and herpes accompanying pains along ganglions (herpes zoster). Herpes diseases tend to increase according to aging, stress, and an increase in AIDS patients, becoming a major social issue.
There are no topical products specifically approved for the treatment of herpes zoster in the US. Commercially available products as anti-herpes virus agents are famciclovir, valacyclovir and acyclovir, which are intravenously or orally administered. The labeling for Famvir (famciclovir) states that the product was not studied in immunocompromised patients with herpes zoster and includes as a precaution the statement: “The efficacy of Famvir (famciclovir) has not been established in immunocompromised patients with herpes zoster.” The labeling for Valtrex (valacyclovir) describes clinical trials conducted in immunocompetent (but not immunocompromised) adults with herpes zoster. However, the labeling of Valtrex includes the following warning; thrombocytopenic purpura/hemolytic uremic syndrome, in some cases resulting in death, has occurred in patients with advanced HIV disease and also in allogenic bone marrow transplant and renal transplant recipients participating in clinical trials. The labeling for Zovirax (acyclovir) tablets describes clinical trials conducted in immunocompetent (but not immunocompromised) adults with herpes zoster. Intravenous acyclovir is the only product currently indicated for treatment of herpes zoster in immunocompromised patients.
Japanese Patent Publication No. 48160/1982 (U.S. Pat. No. 4,386.076) discloses that 5-[(E)-2-halogenovinyl]-arabinofuranosyluracil possesses potent antiviral activity. Of these uracils, 1-β-D-arabinofuranosyl-5-[(E)-2-bromovinyl]uracil (nonproprietary name: sorivudine:BVAU) has an extremely potent antiviral activity against HSV-1, EBV and VZV. This sorivudine was sold under the trade name of “Usevir” as tablets in Japan in 1993. As it was developed as an oral agent, patients administered sorivudine and fluorouracil-based anticancer drugs at the same time died because of the adverse effect due to drug interaction, which was a major problem. Later studies clarified the mechanism of interaction. The mechanism is one in which bromovinyluracil (BVU) as a principal metabolite of sorivudine inhibits the metabolism of fluorouracil and the concentration of fluorouracil in blood rises abnormally, causing serious myelo-suppression such as leucopenia and thrombocytopenia as adverse effects of this anti-cancer drug.
When drugs are administered orally, large amounts are administered for the agents to reach the targeted area. When sorivudine is orally administered in large amounts, a large portion of this as is absorbed by the intestines is discharged in urine through the kidneys. In the intestines, another portion of this drug is metabolized into bromovinyluracil (BVU) by intestinal bacteria and re-absorbed. The re-absorbed BVU inhibits dihydropyrimidine dehydrogenase (DPD) as a metabolic enzyme for fluorouracil. Therefore, the metabolism of fluorouracil is suppressed and its toxicity increased.
Thus, sorivudine is not currently used because of serious drug interaction with fluorouracil based anticancer drugs.
On the other hand, it was reported that the application of sorivudine to the skin suppresses the skin symptoms caused by inoculation with HSV-1 in mice (Antiviral Research, 21, 47-57, 1993). However, it is not disclosed that the topical application of sorivudine is effective for the treatment or prevention of herpes zoster. In the past, animal experimental model for herpes zoster could not be constructed and therefore therapeutic efficacies for herpes zoster could not be demonstrated. Furthermore, 5-[(E)-2-halogenovinyl]-arabinofuranosyluracil including sorivudine is slightly soluble and therefore the topical preparation for practical use was difficult to make. Additionally, interaction of these compounds with fluorouracil-based agents has not been investigated when used as a topical preparation.